The present invention relates to novel azole compounds having an antifungal action, their production and their use.
Various azole compounds having an antifungal action have hitherto been known. For example, Japanese Patent Kokai Publication No. Hei 6-293740 discloses an azole compound represented by the formula: 
(wherein Ar is a substituted phenyl group; R1 and R2 independently are a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; R3 is a group bonded through a carbon atom; R4 is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; and Y and Z independently are a nitrogen atom or a methine group which may optionally be substituted with a lower alkyl group) or a salt thereof. Japanese Patent Kokai Publication No. Hei 8-104676 discloses a compound represented by the formula: 
(wherein Ar is an optionally substituted phenyl; R1 and R2 are, the same or different, a hydrogen atom or a lower alkyl group, or R1 and R2may combine together to form a lower alkylene group; R3 is a hydrogen atom or an acyl group; Y is a nitrogen atom or a methine group; and A is an optionally-substituted saturated cyclic amide group bonded through a first nitrogen atom) and salts thereof. WO 9625410 A1 (corresponding to Japanese Patent Kokai Publication No. Hei 9-183769) discloses a compound represented by the formula: 
[wherein Ar is an optionally substituted phenyl group; R1 and R2, the same or different, are a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; R3 is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; A is Yxe2x95x90Z (Y and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer of 0 to 2; and Az is an optionally substituted azolyl group] or a salt thereof.
On the other hand, a series of compounds referred to as a soft drug have hitherto been known as a quaternary ammonium salt type derivative of an azole (imidazole, triazole) compound which is hydrolyzed enzymatically and/or non-enzymatically. For example, quaternary ammonium salt derivatives of 1-methylimidazole are reported in Journal of Medicinal Chemistry, Vol. 23, page 469, 1980 (antibacterial activity), ibid., Vol. 23, 566, 1980 (antitumor activity), ibid., Vol. 23, 474, 1980 (anticholinergic activity) and ibid., Vol. 32, 493, 1989 (acetylcholine esterase reactivation activity), and these quaternary salts themselves have a biological activity and it is one of their features that hydrolysis thereof occurs rapidly. On the other hand, a quaternary ammonium salt type derivative of azole compounds as a kind of prodrug has been reported only in Pharmaceutical Research Vol. 9, page 372, 1992 (antiglaucoma drug) and Entomologia Experimentalis et Aplicata, Vol. 44, page 295, 1987 (insecticide). In addition, an example of use as a synthetic intermediate of a quaternary ammonium type derivative of imidazole, utilizing its easily hydrolysable property, is reported in Journal of Chemical Society Perkin I, page 1341, 1979 and New Journal of Chemistry, Vol. 16, page 107, 1992. Moreover, a series of quaternary ammonium salt type derivatives are described in U.S. Pat. Nos. 4,061,722 and 4,160,099. However, enzymatically and/or non-enzymatically hydrolyzed quaternary salt derivatives of the azole compounds having an antifungal activity have never been disclosed.
Regarding the azole compounds having the above antifungal activity, the solubility in water for use as an injection preparation is not always sufficient, and it is hard to say that internal absorption is sufficient for demonstrating high therapeutic effect. Therefore, an improvement in solubility in water and in internal absorption have been desired.
Under these circumstances, the present inventors have studied intensively. As a result, the present inventors have found that a derivative prepared by quaternizing nitrogen atoms contained in a 1H-imidazol-1-yl group or 1H-1,2,4-triazol-1-yl group of azole compounds has an improved solubility in water, and is enzymatically and/or non-enzymatically hydrolyzed to produce a compound which has a 1H-imidazol-1-yl group or 1H-1,2,4-triazol-1-yl group and has an antifungal activity. Thus, the present invention has been accomplished based on this finding.
Namely, the present invention relates to a quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound wherein one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo and the substituent can be eliminated in vivo to be converted into an antifungal azole compound; a method for producing the same; and a pharmaceutical composition containing the compound.
The above xe2x80x9cquaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound wherein one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo and the substituent can be eliminated in vivo to be converted into an antifungal azole compound xe2x80x9c[hereinafter referred to as a compound (I),]xe2x80x9d is a compound having an imidazol-1-yl or 1,2,4-triazol-1-yl group in the molecule, in which the nitrogen atom is quaternized by having a substituent in the nitrogen atom at the 3-position of the imidazol-1-yl group and the nitrogen atom at the 2- or 4-position of the 1,2,4-triazol-1-yl group, and the substituent is hydrolyzed in vivo to eliminate, thereby being converted into a compound which has an imidazol-1-yl group or 1,2,4-triazol-1-yl group having no quaternized nitrogen atom and has an antifungal action.
Examples of such a compound include a compound represented by the formula: 
(wherein Q represents an imidazol-1-yl or 1,2,4-triazol-1-yl group in which one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo; Ar represents an optionally substituted phenyl group; A represents an optionally substituted hydrocarbon or an optionally substituted heterocyclic group; X1 represents an oxygen atom or a methylene group; X2 represents an optionally oxidized sulfur atom; m and p respectively represent 0 or 1; Yxe2x88x92 represents an anion; and {circle around (1)} R3, R4 and R5 may be the same or different and represent a hydrogen atom or a lower alkyl group, or {circle around (2)} R3 represents hydrogen atom or a lower alkyl group, and R4 and R5 are combined with each other to represent a lower alkylene group, or {circle around (3)} R5 represents a hydrogen atom or a lower alkyl group, and R3 and R4 are combined with each other to represent a lower alkylene group) or a salt thereof [hereinafter referred to as a compound (Ia), sometimes].
xe2x80x9cA substituent capable of being eliminated in vivoxe2x80x9d in the xe2x80x9cimidazol-1-yl or 1,2,4-triazol-1-yl group in which one of nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivoxe2x80x9d represented by Q may be any group which is eliminated in vivo, and the group represented by Q includes those represented by the formula (II): 
(wherein R1 represents an optionally substituted hydrocarbon group or heterocyclic group; R 2represents a hydrogen atom or a lower alkyl group; X represents a nitrogen atom or a methine group; and n represents 0 or 1).
Examples of the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 includes aliphatic hydrocarbon group, aromatic hydrocarbon group and aromatic-aliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group include alkyl group, cycloalkyl group, cycloalkylalkyl group, alkenyl group and alkynyl group. Examples of the alkyl group include straight-chain or branched alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc., and among them, lower alkyl group having 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.) is particularly preferable. Examples of the cycloalkyl group include cycloalkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc., and among them, cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is particularly preferable. Examples of the cycloalkylalkyl group include those having 4 to 12 carbon atoms, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc., and among them, cycloalkylalkyl group having 6 to 8 carbon atoms (e.g. cyclopentylmethyl, cyclohexylmethyl, etc.) is particularly preferable. Examples of the alkenyl group include those having 2 to 4 carbon atoms, such as vinyl, propenyl, butenyl, etc., and among them, alkenyl having 2 to 3 carbon atoms (e.g. vinyl, propenyl) is particularly preferable. Examples of the alkynyl group include those having 2 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc., and among them, alkynyl having 2 to 3 carbon atoms (e.g. ethynyl, propynyl) is particularly preferable.
Examples of the aromatic hydrocarbon group include those having 6 to 14 carbon atoms, such as phenyl, naphthyl, biphenylyl, anthryl, indenyl, etc., and among them, aryl group having 6 to 10 carbon atoms (e.g. phenyl, naphthyl, etc.) is particularly preferable.
Examples of the aromatic-aliphatic hydrocarbon group include aralkyl groups having 7 to 15 carbon atoms, such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, indanyl, indanylmethyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthylmethyl, etc., and among them, aralkyl groups having 7 to 11 carbon atoms (e.g. benzyl, phenethyl, naphthyl-methyl, etc.) are particularly preferable.
The xe2x80x9cheterocyclic groupxe2x80x9d of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 is a group obtained by removing one of hydrogen atoms linked to a heterocyclic ring, and such a heterocyclic ring represents a 5- to 8-membered ring containing 1 to several, preferably 1 to 4 hetero atoms (e.g. nitrogen atom (optionally oxidized), oxygen atom, sulfur atom, etc.), or a condensed ring thereof. Specific examples of the heterocyclic ring group include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl and the like.
Examples of the substituent in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 include heterocyclic group, oxo group, hydroxy group, C1-6 alkoxy group, C3-10 cycloalkyloxy group, C6-10 aryloxy group, C7-19 aralkyloxy group, heterocyclic ring-oxy group, mercapto group, C1-6 alkylthio group (sulfur atom may be oxidized), C3-10 cycloalkylthio group (sulfur atom may be oxidized), C6-10 arylthio group (sulfur atom may be oxidized), C7-19 aralkylthio group (sulfur atom may be oxidized), a heterocyclic ring-thio group, a heterocyclic ring-sulfinyl group, a heterocyclic ring-sulfonyl group, an amino group, mono-C1-6 alkylamino group, di-C1-6 alkylamino group, tri-C1-6 alkylammonio group, C3-10 cycloalkylamino group, C6-10 arylamino group, C7-19 aralkylamino group, heterocyclic ring-amino group, cyclic amino group, nitro group, halogen atom, cyano group, carboxyl group, C1-10 alkoxy-carbonyl group, C6-10 aryloxy-carbonyl group, C7-19 aralkyloxy-carbonyl group, C6-10 aryl-carbonyl group, C1-6 alkanoyl group, C3-5 alkenoyl group, C6-10 aryl-carbonyloxy group, C2-6 alkanoyloxy group, C3-5 alkenoyloxy group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted carbamoyloxy group, C1-6 alkanoylamino group, C6-10 aryl-carbonylamino group, C1-10 alkoxy-carboxamido group, C6-10 aryloxy-carboxamido group, C7-19 aralkyloxy-carboxamido group, C1-10 alkoxy-carbonyloxy group, C6-10 aryloxy-carbonyloxy group, C7-19 aralkyloxy-carbonyloxy group, C3-10 cycloalkyloxy-carbonyloxy group, optionally substituted ureido group, etc., and they may be the same or different and 1 to 4 substituents may be present. Examples of the xe2x80x9cC1-6 alkoxy groupxe2x80x9d include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, etc.; xe2x80x9cexamples of the C3-10 cycloalkyloxy groupxe2x80x9d include cyclopropyloxy, cyclohexyloxy, etc.; examples of the xe2x80x9cC6-10 aryloxy groupxe2x80x9d include phenoxy, naphthyloxy, etc.; examples of the xe2x80x9cC7-19 aralkyloxy groupxe2x80x9d include benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy, etc.; examples of the xe2x80x9cC1-6 alkylthio group (sulfur atom may be oxidized)xe2x80x9d include methylthio, ethylthio, n-propylthio, n-butylthio, methylsulfinyl, methysulfonyl, etc.; examples of the xe2x80x9cC3-10 cycloalkylthio group (sulfur atom may be oxidized)xe2x80x9d include cyclopropylthio, cyclohexylthio, cyclopentylsulfinyl, cyclohexylsulfonyl, etc.; examples of the xe2x80x9cC6-10 arylthio group (sulfur atom may be oxidized)xe2x80x9d include phenylthio, naphthylthio, phenylsulfinyl, phenylsulfonyl, etc.; examples of the xe2x80x9cC7-19 aralkylthio group (sulfur atom may be oxidized)xe2x80x9d include benzylthio, phenylethylthio, benzhydrylthio, benzylsulfinyl, benzylsulfonyl, etc.; examples of the xe2x80x9cmono-C1-6 alkylamino groupxe2x80x9d include methylamino, ethylamino, n-propylamino, n-butylamino, etc.; examples of the xe2x80x9cdi-C1-6 alkylamino groupxe2x80x9d include dimethylamino, diethylamino, methylethylamino, di-(n-propyl)amino, di-(n-butyl)amino, etc.; examples of the xe2x80x9ctri-C1-6 alkylammonio groupsxe2x80x9d include trimethylammonio, etc.; examples of the xe2x80x9cC3-10 cycloalkylamino groupxe2x80x9d include cyclopropylamino, cyclopentylamino, cyclohexylamino, etc.; examples of the xe2x80x9cC6-10 arylamino groupxe2x80x9d include anilino, N-methylanilino, etc.; examples of the xe2x80x9cC7-19 aralkylamino groupxe2x80x9d include benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, etc.; examples of the xe2x80x9ccyclic amino groupxe2x80x9d include 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, etc.; examples of the xe2x80x9chalogen atomxe2x80x9d include fluorine, chlorine, bromine, iodine, etc.; examples of the xe2x80x9cC1-10 alkoxy-carbonyl groupxe2x80x9d include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl, etc.; xe2x80x9cC6-10 aryloxy-carbonyl groupxe2x80x9d include phenoxycarbonyl, naphthyloxycarbonyl, etc.; examples of the xe2x80x9cC7-19 aralkyloxy-carbonyl groupxe2x80x9d include benzyloxycarbonyl, benzhydryloxycarbonyl, etc.; examples of the xe2x80x9cC6-10 aryl-carbonyl groupxe2x80x9d include benzoyl, naphthoyl, phenylacetyl, etc.; examples of the xe2x80x9cC1-6 alkanoyl groupxe2x80x9d include formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc.; examples of the xe2x80x9cC3-5 alkenoyl groupxe2x80x9d include acryloyl, crotonoyl, etc.; examples of the xe2x80x9cC6-10 aryl-carbonyloxy groupxe2x80x9d include benzoyloxy, naphthoyloxy, phenylacetoxy, etc.; examples of the xe2x80x9cC2-6 alkanoyloxy groupxe2x80x9d include acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, etc.; examples of the xe2x80x9cC3-5 alkenoyloxy groupxe2x80x9d include acryloyloxy, crotonoyloxy, etc.; examples of the xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d include carbamoyl group which may be substituted with one or two substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.), phenyl group, C1-7 acyl group (e.g. acetyl, propionyl, benzoyl, etc.) and C1-4 alkoxy-phenyl group (e.g. methoxyphenyl, etc.), and cyclic aminocarbonyl group, and specific examples thereof include carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl, etc.; examples of the xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d include thiocarbamoyl groups which may be substituted by one or two substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.) and phenyl group, and specific examples thereof include thiocarbamoyl, N-methylthiocarbamoyl, N-phenylthiocarbamoyl, etc.; examples of the xe2x80x9coptionally substituted carbamoyloxy groupxe2x80x9d include carbamoyloxy groups which may be substituted with one or two substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.) and phenyl group, and specific examples thereof include carbamoyloxy, N-methylcarbamoyloxy, N,N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy, etc.; examples of the xe2x80x9cC1-6 alkanoylamino groupxe2x80x9d include acetamido, propionamido, butyramido, valelamido, pivalamido, etc.; examples of the xe2x80x9cC6-10 aryl-carbonylamino groupxe2x80x9d benzamido, naphthamido, phthalimido, etc.; examples of the xe2x80x9cC1-10 alkoxy-carboxamido groupxe2x80x9d include methoxycarboxamido (CH3 OCONHxe2x80x94), ethoxycarboxamido, tert-butoxycarboxamido, etc.; examples of the xe2x80x9cC6-10 aryloxy-carboxamido groupxe2x80x9d include phenoxycarboxamido(C6H5OCONHxe2x80x94), etc.; examples of the xe2x80x9cC7-10 aralkyloxy-carboxamido groupxe2x80x9d include benzyloxycarboxamido(C6H5CH2OCONHxe2x80x94), benzhydryloxycarboxamido, etc.; examples of the xe2x80x9cC1-10alkoxy-carbonyloxy groupxe2x80x9d include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, tert-butoxycarbonyloxy, n-pentyloxycarbonyloxy, n-hexyloxycarbonyloxy, etc.; examples of the xe2x80x9cC6-10 aryloxy-carbonyloxy groupxe2x80x9d include phenoxycarbonyloxy, naphthyloxycarbonyloxy, etc.; examples of the xe2x80x9cC7-19 aralkyloxy-carbonyloxy groupxe2x80x9d include benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, benzhydryloxycarbonyloxy, etc.; examples of the xe2x80x9cC3-10 cycloalkyloxy-carbonyloxy groupxe2x80x9d include cyclopropyloxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.; and examples of the xe2x80x9coptionally substituted ureido groupxe2x80x9d include ureido group which may be substituted with 1 to 3 substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.), phenyl group, etc., and specific examples thereof include ureido, 1-methylureido, 3-methylureido, 3,3-dimethylureido, 1,3-dimethylureido, 3-phenylureido, etc.
As the substituent of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1, for example, C1-6 alkyl group, C3-6 cycloalkyl group, C4-7 cycloalkylalkyl group, C2-3 alkenyl group, C2-3 alkynyl group, C6-10 aryl group, C7-11 aralkyl group, etc. are used, in addition to those described above. Examples of the xe2x80x9cC1-6 alkyl groupxe2x80x9d include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.; examples of the xe2x80x9cC3-6 cycloalkyl groupxe2x80x9d include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; examples of the xe2x80x9cC4-7 cycloalkylalkyl groupxe2x80x9d include cyclopropylmethyl, cyclopentylmethyl, etc.; examples of the xe2x80x9cC2-3 alkenyl groupxe2x80x9d include vinyl, propenyl, etc.; examples of the xe2x80x9cC2-3 alkynyl groupxe2x80x9d include ethynyl, propynyl, etc.; examples of the xe2x80x9cC6-10 aryl groupxe2x80x9d include phenyl, naphthyl, etc.; and examples of the xe2x80x9cC7-11 aralkyl groupxe2x80x9d include benzyl, phenethyl, naphthylmethyl, etc. The number of these substituents of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted hetercyclic groupxe2x80x9d.
The heterocyclic group in the substituent of the xe2x80x9chydrocarbon groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d, and the heterocyclic group in the heterocyclic ring-oxy group, heterocyclic ring-thio group, heterocyclic ring-sulfinyl group, heterocyclic ring-sulfonyl group and heterocyclic ring-amino group respectively represent a group obtained by removing one of the hydrogen atoms linked to the heterocyclic ring, and such heterocyclic ring represents a 5- to 8-membered ring containing 1 to several, preferably 1 to 4 hetero atoms (e.g. nitrogen atom (optionally oxidized), oxygen atom, sulfur atom, etc.), or a condensed ring thereof. Examples of the heterocyclic group include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, etc. These heterocyclic group may be substituted with 1 to 3 substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.), hydroxyl group, oxo group and C1-4 alkoxy group (e.g. methoxy, ethoxy, etc.).
In the optionally substituted hydrocarbon group or heterocyclic group represented by R1, as the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d, C1-6 alkyl group (examples of the C1-6 alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.) which may be substituted with 1 to 3 substituents selected from hydroxyl, C1-6 alkoxy group, C7-19 aralkyloxy group, C1-6 alkylthio group, C1-6 alkylsulfonyl, C1-6 alkanoylamino group, C1-10 alkoxy-carbonyl group, C7-19 aralkyloxy-carbonyl group, optionally substituted carbamoyl group, C1-10 alkoxy-carboxamido, C7-10 aralkyloxy-carboxamido and heterocyclic group (optionally substituted) is preferable, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 1,3-dibenzyloxy-2-propyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, methylthiomethyl, methylsulfonylethyl, acetamidomethyl, 1-acetamidoethyl, 2-acetamidoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-ethoxycarbonylethyl, 2-ethoxycarbonylethyl, 1-methoxycarbonyl-1-methylethyl, 1-ethoxycarbonyl-1-methylethyl, 1-tert-butoxycarbonyl-1-methylethyl, 1-benzyloxycarbonylethyl, 1-benzyloxycarbonyl-1-methylethyl, carbamoylmethyl, N,N-dimethylcarbamoylmethyl, methoxycarboxamidomethyl, ethoxycarboxamidomethyl, tert-butoxycarboxamidomethyl, benzyloxycarboxamidomethyl, 2-ethoxycarboxamidoethyl, 2-furylmethyl, 2-tetrahydrofurylmethyl, 1,3-dioxolan-2-ylmethyl, 1,3-dioxolan-4-ylmethyl, 2-oxo-1,3-dioxolan-4-ylmethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, 1,3-dioxan-5-ylmethyl, 1-ethoxycarbonyl-1-(2,3,4-trihydroxyphenyl)methyl, 1-acetamido-2-ethoxycarbonyl, 1-acetamido-3-ethoxycarbonylpropyl, 2-acetamido-2-ethoxycarbonylethyl, 3-acetamido-3-ethoxycarbonylpropyl, 1-acetamido-2-carbamoylethyl, 1-acetamido-3-carbamoylpropyl, etc.
Among the above C1-6 alkyl groups which may be substituted with 1 to 3 substituents, the most preferable ones include straight-chain or branched C1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.; and straight-chain or branched C1-4 alkyl group substituted with hydroxyl group, C1-6 alkoxy group, C1-10 alkoxy-carbonyl group, heterocyclic group (optionally substituted), etc., such as 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methoxyethyl, 2-ethoxyethyl, 3-benzyloxypropyl, ethoxycarbonylmethyl, 1-ethoxycarbonylethyl, 1-benzyloxycarbonylethyl, 2-furylmethyl, 2-tetrahydrofurylmethyl, 1,3-dioxolan-4-ylmethyl, 2-oxo-1,3-dioxolan-4-ylmethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, etc.
In the optionally substituted hydrocarbon group or heterocyclic group represented by R1, as the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d, a heterocyclic group substituted with 1 to 3 substituents selected from oxo group, hydroxyl group, C1-6 alkyl group, C1-6 alkoxy group, etc. are preferable, and specific examples thereof include furyl, thienyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, methylfuryl, hydroxyfuryl, methylthienyl, methoxyfuryl, 2-oxo-1,3-dioxolyl, 2,2-dimethyl-1,3-dioxolyl, 2-oxo-1,3-dioxolanyl, 2,2-dimethyl-1,3-dioxolanyl, 2-oxo-1,3-dioxanyl, 2,2-dimethyl-1,3-dioxanyl, etc. Among them, furyl, thienyl, dioxanyl, 2-oxo-1,3-dioxanyl, 2,2-dimethyl-1,3-dioxanyl are particularly preferable.
Examples of the lower alkyl group represented by R2 include lower alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), and methyl is particularly preferable.
As R2, a hydrogen atom or methyl is particularly preferable.
X represents a nitrogen atom or a methine group, and a nitrogen atom is preferable.
Examples of the optionally oxidized sulfur atom represented by X2 includes thio, sulfinyl and sulfonyl.
m and p respectively represent an integer of 0 or 1, and the care where both of them are 0 is preferable.
Examples of the substituent in the xe2x80x9coptionally substituted phenyl groupxe2x80x9d represented by Ar include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), halogenated lower (C1-4) alkyl group (e.g. fluoromethyl, trifluoromethyl, chloromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, etc.) and halogenated lower (C1-4 ) alkoxy group (e.g. fluoromethoxy, trifluoromethoxy, chloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, etc.). The substituent is preferably a halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), more preferably fluorine. The number of substituents is preferably 1 to 3, more preferably 1 to 2.
Preferred examples of Ar include halogenophenyl group, halogenated lower (C1-4 ) alkylphenyl group, halogenated lower (C1-4) alkoxyphenyl group, etc. Examples of the halogenophenyl group include 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-bromophenyl, etc. Examples of the halogenated lower (C1-4) alkylphenyl group include 4-trifluoromethylphenyl, etc. Examples of the halogenated lower (C1-4) alkoxyphenyl group include 4-trifluoromethoxyphenyl, 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-(2,2,3,3,3-pentafluoropropoxy)phenyl, etc.
Specifically preferable examples of Ar is a phenyl group substituted with 1 to 2 halogens, such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl, etc. Among them, a phenyl group substituted with 1 to 2 fluorine atoms, such as 4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, etc. is particularly preferable, and 2-fluorophenyl and 2,4-difluorophenyl are more preferable.
An anion represented by Yxe2x88x92 is that obtained by removing one proton from an organic acid or an inorganic acid, and examples of the organic acid include acetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, etc., and examples of the inorganic acid include hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, water, etc. As Yxe2x88x92, an anion obtained by removing one proton from an inorganic acid is preferable. Among them, an anion obtained by removing one proton from a hydro-halogenoic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, etc. is preferable, and an anion obtained by removing one proton from hydrochloric acid, hydrobromic acid, hydroiodic acid, etc. is particularly preferable. Yxe2x88x92 can be defined as a group having a negative charge, and preferred examples thereof include Clxe2x88x92, Fxe2x88x92, Brxe2x88x92, Ixe2x88x92, HSO3xe2x88x92, HSO4xe2x88x92, H2PO4xe2x88x92, OHxe2x88x92, etc. Among them, Clxe2x88x92, Fxe2x88x92, Brxe2x88x92, Ixe2x88x92 are preferable, and Clxe2x88x92, Brxe2x88x92 and Ixe2x88x92 are particularly preferable.
Examples of the lower alkyl group represented by R3, R4 and R5 include straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Among them, methyl is particularly preferable.
When R3 and R4, or R4 and R5 are combined to form a lower alkylene group, examples of the lower alkylene group include those having 1 to 4 carbon atoms, such as methylene, ethylene, propylene, butylene, etc. When R3 and R4 are combined to form a lower alkylene group, methylene and ethylene are preferable. When R4 and R5 are combined to form a lower alkylene group, ethylene is preferable.
R3 is preferably a hydrogen atom. Preferably, R4 and R5 are simultaneously hydrogen atoms or methyl groups, or one of them is a hydrogen atom and the other one is a methyl group. More preferably, one of R4 and R5 is a hydrogen atom and the other one is methyl.
Examples of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d or xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by A includes the same one as that described for R1. A is preferably a group of the formula: 
(wherein R6 represents an optionally substituted hydrocarbon group or aromatic heterocyclic group; and Z represents an optionally substituted lower alkylene group or a group of the formula:
xe2x80x94Dxe2x95x90Exe2x80x94
(D and E may be same or different and represent a nitrogen atom or a methine group which may be substituted with a lower alkyl)). Examples of the hydrocarbon group in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R6 include aliphatic hydrocarbon group, aromatic hydrocarbon group and aromatic-aliphatic hydrocarbon group.
Examples of the aliphatic hydrocarbon group include alkyl, cycloalkyl, alkenyl, alkynyl group, etc. Examples of the alkyl groups include straight-chain or branched one having 1 to 12 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl, octyl, nonyl, decyl, dodecyl, etc. Among them, a lower alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.) is particularly preferable. Examples of the cycloalkyl groups include cycloalkyl groups having 3 to 8 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Among them, a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is particularly preferable. Examples of the alkenyl group include alkenyl group having 2 to 4 carbon atoms. Specific examples thereof include vinyl, propenyl, butenyl, etc. Among them, an alkenyl group having 2 to 3 carbon atoms (e.g. vinyl, propenyl, etc.) is particularly preferable. Examples of the alkynyl group include alkynyl group having 2 to 4 carbon atoms. Specific examples thereof include ethynyl, propynyl, butynyl, etc. Among them, an alkynyl group having 2 to 3 carbon atoms (e.g. ethynyl, propynyl, etc.) is particularly preferable.
Examples of the aromatic hydrocarbon group include aryl group having 6 to 14 carbon atoms. Examples of the aryl group include phenyl, naphthyl, biphenylyl, anthryl, indenyl, etc. Among them, an aryl group having 6 to 10 carbon atoms (e.g. phenyl, naphthyl, etc.) is particularly preferable.
Examples of the aromatic-aliphatic hydrocarbon group include arylalkyl groups having 7 to 15 carbon atoms. Specific examples thereof include benzyl, phenethyl, phenylpropyl, naphthylmethyl, indanyl, indanylmethyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthylmethyl, biphenylmethyl, benzhydryl, etc. Among them, an aralkyl group having 7 to 11 carbon atoms (e.g. benzyl, phenethyl, naphthylmethyl, etc.) is particularly preferable.
Examples of the aromatic heterocyclic group in the xe2x80x9caromatic heterocyclic group which may have a substituentxe2x80x9d represented by R6 include aromatic heterocyclic group containing at least one hetero atom selected from nitrogen atom, sulfur atom and oxygen atom. The aromatic heterocyclic group may be condensed with a benzene ring, or 5- or 6-membered heterocyclic ring. Examples of the aromatic heterocyclic group include aromatic heterocyclic group such as imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl, pyrazinyl, pyrimidinyl, oxazolyl, isooxazolyl, etc.; and condensed aromatic heterocyclic group such as benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, etc. As the aromatic heterocyclic group, a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 hetero atoms selected optionally from nitrogen atom, sulfur atom and oxygen atom (e.g. imidazolyl, triazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, etc.) is particularly preferable.
Examples of the substituent in the xe2x80x9caliphatic, aromatic or aromatic-aliphatic hydrocarbon group which may have a substituent, or aromatic heterocyclic group which may have a substituentxe2x80x9d represented by R6include hydroxyl group, optionally esterified carboxyl group (e.g. carboxyl, alkoxycarbonyl having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.), nitro group, amino group, acylamino group (e.g. alkanoylamino having 1 to 10 carbon atoms, such as acetylamino, propionylamino, butyrylamino, etc.), amino group which is mono- or di-substituted with an alkyl group having 1 to 10 carbon atoms (e.g. methylamino, dimethylamino, diethylamino, dibutylamino, etc.), optionally substituted 5- to 6-membered cyclic amino group (e.g. pyrrolidinyl, morpholino, piperidino, pyrazolidinyl, perhydroazepinyl, piperazinyl, 4-benzylpiperazinyl, 4-acetylpiperazinyl, 4-(4-trifluoromethoxyphenyl)-1-piperazinyl, 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-piperazinyl, 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl, 4-[4-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl, 4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-1-piperazinyl, 4-(4-trifluoromethylphenyl)-4-piperazinyl, etc.), alkoxy group having 1 to 6 carbon atoms (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), halogen atom (e.g. fluorine, chlorine, bromine, etc.), alkyl group having 1 to 6 carbon atoms (e.g. methyl, propyl, butyl, etc.), cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl, cyclopentyl, etc.), halogeno-alkyl group having 1 to 6 carbon atoms (e.g. trifluoromethyl, dichloromethyl, trifluoroethyl, etc.), halogeno-alkoxy group having 1 to 6 carbon atoms (e.g. trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy, 2-fluoroethoxy, etc.), oxo group, thioxo group, mercapto group, alkylthio group having 1 to 6 carbon atoms (e.g. methylthio, ethylthio, butylthio, etc.), alkylsulfonyl group having 1 to 6 carbon atoms (e.g. methanesulfonyl, ethanesulfonyl, butanesulfonyl, etc.), alkanoyl group having 1 to 10 carbon atoms (e.g. acetyl, formyl, propionyl, butyryl, etc.), 5- or 6-membered aromatic heterocyclic group (e.g. pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyridazinyl, etc.) and condensed aromatic heterocyclic group (e.g. benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, indolyl, etc.). Among them, a halogeno-alkoxy group having 1 to 6 carbon atoms and 5-membered aromatic heterocyclic group is preferable, and 1,1,2,2-tetrafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, pyrazolyl (e.g. 1H-pyrazol-1-yl), imidazolyl (e.g. 1H-imidazol-1-ly), 1,2,3-triazolyl (e.g. 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl), 1,2,4-triazolyl (e.g. 1H-1,2,4-triazol-1-yl), tetrazolyl (e.g. 1H-tetrazol-1-yl, 2H-tetrazol-2-yl) are particularly preferable.
The number of the above substituents is preferably 1 to 3, more preferably 1 to 2.
The aliphatic, aromatic or aromatic-aliphatic hydrocarbon groups which may have a substituent, or aromatic heterocyclic group which may have a substituent, which is represented by R6, is preferably an aromatic hydrocarbon group which may have a substituent, more preferably a phenyl group having a substituent. Among them, a phenyl group substituted with a halogeno-alkoxy group having 1 to 6 carbon atoms (e.g. 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl) and a phenyl group substituted with a 5-membered aromatic heterocyclic group [e.g. 4-(1H-pyrazol-1-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(1H-1,2,3-triazol-1-yl)phenyl, 4-(2H-1,2,3-triazol-2-yl)phenyl, 4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl, 4-(2H-tetrazol-2-yl)phenyl] are particularly preferable.
The lower alkylene group in the xe2x80x9coptionally substituted lower alkylene groupxe2x80x9d represented by Z include those having 1 to 3 carbon atoms, such as methylene, ethylene, propylene, etc. Among them, ethylene is particularly preferable. The substituent in the xe2x80x9coptionally substituted lower alkylene groupxe2x80x9d is preferably a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. Among them, methyl and ethyl are more preferable, and methyl is particularly preferable.
Preferred examples of the ethylene group which may be substituted with a lower alkyl group, which is represented by Z, include ethylene, 1-methylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-ethylethylene, 1,2-diethylethylene, etc. Among them, ethylene is particularly preferable.
When Z is Dxe2x95x90E, examples of lower alkyl group in the xe2x80x9cmethine group which may be substituted with a lower alkyl groupxe2x80x9d represented by D or E include straight-chain or branched alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). Among them, methyl is preferable.
Preferred examples of the methine group which may be substituted with a lower alkyl group, represented by D or E, include methine, ethylidyne (xe2x80x94C(CH3)xe2x95x90), propylidyne (xe2x80x94C(CH2CH3)xe2x95x90), butylidyne (xe2x80x94C(CH2CH2CH3)xe2x95x90), etc. Among them, methine and ethylidyne are preferable, and methine is particularly preferable.
The case where one of D and E is a nitrogen atom and the other is methine; the case where both of D and E are methines; the case where both of D and E are nitrogen atoms; and the case where one of D and E is a nitrogen atom and the other is ethylidyne are preferable. Among them, the case where one of D and E is a nitrogen atom and the other one is methine; and the case where both of D and E are methines are particularly preferable.
Specifically, Z is preferably xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90C(CH3)xe2x80x94, xe2x80x94C(CH3)xe2x95x90Nxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, etc. Among them, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, etc. are more preferable, and xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 are the most preferable.
As the group represented by the formula: 
for example, 
etc. are preferable. Among them, 
ect. are particularly preferable.
Also, when a reactive atom such as nitrogen atom is present in the optionally substituted hydrocarbon group or optionally substituted heterocyclic group represented by A, a group of formula: 
(wherein each symbol is as defined above) may be linked to the atom.
When the compound (I) has one or more asymmetric carbon atoms in the molecule, two or more stereoisomers exist, and the stereoisomers and a mixture thereof are also involved in the present invention. In the compound represented by the general formula (1a), when Q is a group represented by the formula (II), A is 
m and p are both O, R4 is a hydrogen atom and R5 is a methyl group, an optically active compound in which both carbon to which the optionally substituted phenyl group represented by Ar is linked and carbon to which R5 is linked are in the (R) configuration, is particularly preferable.
In the formula (Ia), when Q is a group represented by the formula (II), the formula (Ia) can also be represented by the formula: 
(wherein each symbol is as defined above).
The compounds of the present invention can be either a hydrate or a nonhydrate. The compounds of the present invention are converted in vivo into compounds having an antifungal activity, represented by the formula: 
(wherein each symbol is as defined above).
Specific examples of the compounds according to the present invention are shown in Tables 1 to 4, but are not limited to the exemplified compounds.
The compounds of the present invention can be produced by introducing a group, which is capable of being eliminated in vivo, into an antifungal compound having an imidazol-1-yl group or 1,2,4-triazol-1-yl group.
Examples of the antifungal compound having an imidazol-1-yl group or 1,2,4-triazol-1-yl group include known azole antifungal compounds such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, D0870, voriconazole, econazole, isoconazole, sulconazole, butoconazole, tioconazole, bifonazole, croconazole, oxiconazole, terconazole, SSY-726, KP-103, Sch-56592, Sch-51048, UR-9746, MFB-1041, UR-9751, UR-9728, UR-9825, ER-30346, T-8581, BAY-W-9279, fenticonazole, omoconazole, flutrimazole, eberconazole, lanoconazole, neticonazole, sertaconazole, genaconazole, etc., but are not limited to known antifungal agents.
The compound (Ia-1) [the compound (Ia) wherein Q is a group represented by the formula (II)], can be produced, for example, by reacting a compound (III) with a compound represented by the formula (IV): 
(wherein Y1 represents a halogen atom and other symbols are as defined above)[hereinafter referred to as a compound (IV), sometimes] and optionally subjecting the reaction product to anion exchange.
The halogen atom represented by Y1 is preferably chlorine, bromine or iodine.
The reaction between the compound (III) and compound (IV) is usually carried out with or without a solvent which does not inhibit the reaction. As the solvent which does not inhibit the reaction, for example, ketones (e.g. acetone, 2-butanone, 2-pentanone, etc.), sulfoxides (e.g. dimethylsulfoxide, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.), nitrites, (e.g. acetonitrile, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons, (e.g. dichlorometbane, chloroform, 1,2-dichloroethane, etc.), esters (e.g. ethyl acetate, etc.), amides (e.g. dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrrolidinone, etc.) and ureylenes (e.g. 1,3-dimethyl-2-imidazolidinone, etc.) are used. These solvents can be used alone or in combination thereof in an appropriate ratio.
The compound (IV) is used in an amount of about 1 to 100 equivalent, preferably about 1 to 5 equivalent, based on the compound (III).
The reaction temperature is not specifically limited, but is usually from about 0 to 150xc2x0 C., preferably from about 20 to 120xc2x0 C.
The reaction time is from several minutes to several hundred hours (e.g. 5 minutes to 100 hours, etc.).
The compound thus obtained can be optionally converted into a compound (Ia) having a desired anion (Yxe2x88x92) by anion exchange. The anion exchange can be carried out by treating with an anion type ion exchange resin, or an alkali metal (e.g. sodium, potassium, etc.) salt of an organic or inorganic acid described above for Yxe2x88x92, in the presence of water, a mixed solvent of water and an organic solvent (e.g. acetone, acetonitorile, tetrahydrofuran, methanol, ethanol, etc.) or organic solvent.
The compound (I) of the present invention (hereinafter referred to as a present compound (I), sometimes) thus obtained can be isolated and purified from the reaction mixture using a per se known means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc.
When the present compound (I) has one or more asymmetric carbon atoms in the molecule, two or more stereoisomers exist, but those isomers can be separately prepared, if desired. For example, when the starting compounds (III) and (IV) have an asymmetric carbon atom in the molecule, a single isomer of the present compound (Ia) can be obtained by carrying out above reaction using such single isomer. In addition, a single isomer of the reaction compound (Ia) can be obtained by carrying out above reaction using a single isomer of the starting compound (III). Also, when the product is a mixture of two or more kinds of isomers, the product can be separated by using a normal separation method, e.g. separation means such as various chromatographies and fractional recrystallization.
When the starting compound (III) of the present invention is a per se known antifungal agent described above, the production method is known and methods of series of compounds which are useful as an antifungal agent are per se known, for example, the methods described in Japanese Patent Kokai Publication No. Hei 6-293740, Japanese Patent Kokai Publication No. Hei 8-104676 and WO-9625410A. In addition, the production method of the other starting compound (IV) is also known, and the compound can be produced by the method described in Synthesis, page 588 (1971) and Synthetic Communications, Vol. 25, page 2739 (1995), or a manner based on the method.
Since the present compound (I) has low toxicity and strong antifungal activity to the genus Candida [e.g. Candida albicans, Candida utilis, Candida glabrata, etc.], genus Histoplasma [e.g. Histoplasma capsulatum, etc.], genus Aspergillus [e.g. Aspergillus niger, Aspergillus fumigatus, etc.], genus Cryptococcus [e.g. Cryptococcus neoformans, etc.], genus Trichophyton [e.g. Trichophyton rubrum, Trichophton mentagrophytes, etc.], genus Microsporum [e.g. Microsporum gypseum, etc.], genus Mallassezia [e.g. Mallassezia furfur, etc.], etc., it can be used for prevention or treatment of fungal infections [e.g. mucosal candidiasis (oral thrush, angular stomatitis, vulvovaginal candidiasis, candida balanoposthitis and urethritis), dermal candidiasis (interdigital candidiasis, intertriginous candidiasis, perianal candidiasis, blastomycosis cutis eczematosa, candida onychia, candida paronychia, auricular candidiasis, cutaneous lesion of candida septicaemia, diffuse superficial candidiasis, candida granuloma, congenital cutaneous candidiasis, candidids), chronic mucocutaneous candidiasis and systemic candidiasis (candidiasis of the respiratory tract, candidiasis of the gastrointestinal tract,candida septicaemia, candida endocarditis, candidiasis of the urinary tract, candidiasis of the eye, candidiasis of the central nervous system, articular and bone candidiasis, candida peritonitis, candidiasis of the liver, intrauterine candidiasis, etc.) due to genus Candida; acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis and disseminated histoplasmosis, etc. due to genus Histoplasma; aspergillosis of the respiratory tract (allergic aspergillosis, bronchial aspergillosis, aspergilloma, pulmonary aspergillosis (acute invasive pulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis), aspergillary empyema), disseminated aspergillosis, central nervous system aspergillosis, aspergillary endocarditis, aspergillary myocarditis, aspergillary pericarditis, aspergillary mycetoma, aspergillary otomycosis, aspergillary onychia, aspergillary paronychia, aspergillary keratitis, aspergillary endophthalmitis, cutaneous aspergillosis and nasal-orbital aspergillosis, etc. due to genus Aspergillus; pulmonary cryptococcosis, central nervous system cryptococcosis, cutaneous and mucocutaneous cryptococcosis, osseous cryptococcosis, cryptococcosis of lymphnodes, disseminated cryptococcosis and cryptococcosis of hematopoetic organs, etc. due to genus Cryptococcus; tinea capitis, favus, kerion celsi, tinea barbae, trichophytia maculovesiculosa, trichophytia eczematosa marginata, tinea imbricata, trichophytia pompholyciformis, tinea unguium, trichophitid and granuloma trychophyticum, etc. due to genus Trichophyton or genus Microsporum; tinea versicolor, etc. due to genus Mallassezia] in the mammals (e.g. human, domestic animal, fowl, etc.), and can also be used for prevention or treatment of atopic dermatitis. Moreover, the compound (I) of the present invention can be used as an agricultural antifungal agent.
When the present compound (I) is administered to humans, it can be administered orally or parenterally in safety as a pharmaceutical composition such as oral administration (e.g. powder, granule, tablet, capsule, etc.), parenteral administration [e.g. injection, external agent (e.g. nasal administration, percutaneous administration, etc.) and suppository (e.g. rectal suppository, vaginal suppository, etc.)] alone or in combination with appropriate pharmaceutically acceptable carriers, excipients, diluents, etc.
These preparations can be prepared by a per se known method which is usually used in the production process. The proportion of the present compound (I) in the preparation varies depending on the form thereof, and can be in the range usually employed in the antifungal agent. For example, it is about 10 to 95% by weight in case of the above oral administration and is about 0.001 to 95% by weight in case of the above parenteral administration.
For example, the injection can be prepared by mixing the present compound (I) with dispersants [e.g. Tween 80 (manufactured by Atlas Powder company, U.S.A.), HCO 60 (manufactured by Nikko Chemicals Co.), carboxymethylcellose, sodium alginate, etc.], preservatives (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.) and isotonic agents (e.g. sodium chloride, glycerin, sorbitol, glucose, etc.) to form an aqueous injection, or by dissolving, suspending or emulsifying into vegetable oils (e.g. olive oil, sesame oil, peanut oil, cotton seed oil, corn oil, etc.), propyleneglycol, etc. to form an oily injection.
An oral administration preparation can be prepared by adding excipients (e.g. lactose, sucrose, starch, etc.), disintegrators (e.g. starch, calcium carbonate), binders (e.g. starch, arabic gum, carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropylcellulose, etc.) and lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc.) to the present compound (I), subjecting the mixture to compression molding and optionally masking of taste or coating with a per se known method for the purpose of imparting an enteric property or a sustained-release property. As a coating agent, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethyleneglycol, Tween 80, Pluronic P68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm GmbH and Co. KG, Germany, copolymer of methacrylic acid and acrylic acid) and pigment (e.g. titanium oxide, iron oxide red, etc.) can be used.
The compound (I) of the present invention can be used as a solid, semi-solid or liquid external preparation. For example, the solid external preparation can be prepared by using the present compound (I) as it is, or adding excipients (e.g. glycol, mannitol, starch, microcrystalline cellulose, etc.), thickeners (e.g. natural gums, cellulose derivatives, acrylic polymer, etc.), etc. to the present compound (I), followed by mixing to form a powdered composition. In case of the semi-solid external preparation, it is preferable to use as an aqueous or oily gel agent or an ointment. In case of the liquid external preparation, it can be prepared by forming into an oily or aqueous suspension in nearly the same manner as in case of the injection. To the solid, semi-solid or aqueous external preparation, pH adjustors (e.g. carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.) and preservatives (e.g. paraoxybenzoates, chlorobutanol, benzalkonium chloride, etc.) may be added. Specifically, an ointment containing vaseline, lanoline, etc. as a base, and about 0.1 to 100 mg of the present compound (I) can be used for sterilization or disinfection of skin or mucosa.
The present compound (I) can be formed into an oily or aqueous solid, semi-solid or liquid suppository. In case of preparing the suppository, examples of the oily base include glyceride of higher fatty acid [e.g. cacao butter, Witepsol (manufactured by Dynamite Nobel Company), etc.], medium chain length fatty acid [e.g. migriolic acid (manufactured by Dynamite Nobel Company), etc. ] and vegetable oil [e.g. sesame oil, soy bean oil, cotton seed oil]. Examples of the aqueous base include polyethylene glycols, propylene glycols, etc. and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic polymers, etc.
The dose of the present compound (I) varies depending on the infecting condition and administering route, etc. In case of administering orally to adult (weight 50 kg) patients for the purpose of treating Candidiasis, the dose is about 0.01 to 100 mg/kg/day, preferably about 0.1 to 50 mg/kg/day. More preferably, the dose is about 0.5 to 10 mg/kg/day.
Two or more compounds of the present invention can be used in the preparation of the present invention, and also the compound of the present invention can be used in combination with one or more compound having antifungal activity other than the compound of the present invention. When using the present compound (I) as an agricultural antifungal agent, the present compound (I) is dissolved or suspended in a suitable liquid carrier (e.g. solvent), or mixed with or adsorbed to a suitable solid carrier (e.g. diluent, bulking agent, etc.) and, if necessary, emulsifiers, suspension, spreading agents, osmotic agents, wetting agents, mucilages, stabilizers, etc. are added to form an emulsion, hydrate, powder, granule, etc. These preparations can be prepared by a per se known method. In case of the control of rice blight, an amount of the compound (I) of the present invention used is preferably from about 25 to 150 g, more preferably from about 40 to 80 g per are of the paddy field. The compound of the present invention can be used in combination with other agricultural antifungal agent.
As the liquid carrier, for example, water, alcohols (e.g. methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethylene glycol, etc.), ethers (e.g. dioxane, tetrahydrofuran, etc.), aliphatic hydrocarbons (e.g. kerosene, kerosene oil, fuel oil, etc.), aromatic hydrocarbons (e.g. benzene, toluene, etc.), halogenated hydrocarbon (e.g. methylene chloride, chloroform, etc.), acid amides (e.g. dimethylformamide, dimethylacetamide, etc.), esters (e.g. ethyl acetate, butyl acetate, etc.) and nitrites (e.g. acetonitrile, propionitrile, etc.) can be used, and these liquid carriers can be used alone or in combination thereof at a suitable proportion.
As the solid carrier, for example, vegetable flours (e.g. soy bean flours, tobacco flours, wheat flours, etc. mineral powders (e.g. kaolin, bentonite, etc.), alumina, sulfur powder, active carbon, etc. can be used, and these solid carriers can be used alone or in combination thereof in a suitable proportion.